The present invention relates to a compound selectively binding to a sensory receptor or selectively altering the expression of a sensory receptor for use in a method for treating or preventing a disease associated with a pathologic cellular cytotoxic T cell (CTL) response. Further, the invention relates to means for detecting a sensory receptor for use in a method for diagnosing cellular resistance against CTL response in a patient. The invention further embraces a method for determining the resistance of a cell against a CTL response in vitro and to a method for identifying agents that influence the response of cells to CTLs.
Today, it is well-known that peripheral immune tolerance plays an important role in several diseases such as in cancer and in preventing autoimmune disorders. In cancer patients, tumor cells often use immune-checkpoints to prevent immune-recognition, thereby imposing resistance against immunotherapy (Rabinovich et al., 2007, and Zitvogel et al., 2006). Successful immunotherapy therefore either depends on an efficient stratification of patients according to the immune sensitivity or resistance of their tumors or on the functional blockade of respective immune-checkpoint pathways (Pardoll, 2012).
Many of the most promising therapeutic strategies in treating diseases associated with immune sensitivity and/or the functional blockade of immune-checkpoint pathways are associated with T cell-based immunotherapy typically involving a cytotoxic T lymphocyte (CTL) response such as exemplarily T cell-based cancer immunotherapy. Current state of the art cancer immunotherapies—involving antigen-specific vaccines or adoptive cellular therapies with tumor-specific CTLs—have meanwhile developed protocols to induce functionally potent T cell responses in the patients (Gao et al., 2013).
However, these therapies are faced with the drawback of cancer cell resistance to specific T cell attack (Rabinovich et al., 2007). Indeed, the success of T cell-based cancer immunotherapy is limited by resistance of many tumors against killing by CTLs.
Therefore, today, there are still a non-negligible number of patients not sufficiently responding to T cell-based immunotherapy.
Neither the reason therefore is known nor a satisfying therapeutic approach overcoming such resistance is available so far. Not even satisfying diagnostic approaches to at least enable the provision of a prognosis on the efficiency of a particular immunotherapy are available so far.
It has been attempted to overcome these problems by unraveling the major immune regulatory pathways imposed by CD80/86-CTLA4 and PDL1-PD1 interactions between the tumor and T cells, respectively (Blank et al., 2004, and Chambers et al., 2001). Blocking antibodies against these surface-expressed proteins can boost anti-tumor immunity and have been successfully applied in clinical trials (Brahmer et al., 2012, Topalian et al., 2012, van Elsas et al., 1999, FDA press release of Mar. 25, 2011“FDA approves new treatment for a type of late-stage skin cancer” and Weber, 2007).
Nevertheless, clinical studies have reported a non-negligible number of unresponsive patients lacking the intratumoral expression of these molecules (Topalian et al., 2012). Indeed, synergistic cooperation between several immune-inhibitory pathways maintain immune tolerance against tumors, which might explain why blocking only one immune-checkpoint node can still result in tumor escape (Berrien-Elliott et al., 2013, and Woo et al., 2012). Still, little is known about molecular factors playing an important role in such immune-inhibitory pathways. One reason is that a comprehensive detection of immune-checkpoint molecules is technically challenging due to the lack of a robust high-throughput assay that enables a qualitative as well as quantitative analysis of heterologous cell-to-cell interaction between the tumor and T cells. So far, only few strategies for identifying such molecular factors playing a role in the impairment of a CTL response have been established in the art that rely on interferon-gamma (IFN-γ) release as an indicator of anti-tumor immune activity (Bellucci et al., 2012, and Hill and Martins, 2006). Furthermore, the methods developed so far are rather insufficient because IFN-γ secretion by immune cells alone does not always correlate with cellular cytotoxicity (Bachmann et al., 1999, and Slifka et al., 1999).
As a consequence, so far, only few molecular factors playing a role in the impairment of a CTL response and few immune suppressive ligands have been identified. Therefore, today, there is still an unmet need for identifying such molecular factors and compounds targeting these as molecular target structures.